Viral infections remain a major threat to human health despite our extensive knowledge of the mammalian immune system. Many viruses such as human immune deficiency virus (HIV), members of the herpes virus family and human papilloma virus (HPV) have evolved mechanisms to evade the host immune response. The overall goal of this program project is to define mechanisms of viral evasion of the immune system and to design therapeutic approaches to interfere with these strategies. This project will focus on two families of DNA viruses, i.e. papilloma virus (PV) and herpes virus, specifically HSV-1 (and also HHV-6,-7 and VZV). These two viral families were selected because of their impact on human health and because at present there are no vaccines or cure for either one. HSV evades both the host innate immune system and surveillance by cytotoxic T cells (CTL). Because of the many potential evasion mechanisms that can be employed by viruses, a broad approach is necessary to understand them. Therefore, this program project was designed to combine the expertise of investigators from various disciplines. The first two projects will examine viral evasion of MHC class I and class II pathways. The third and fourth projects will examine the evasion of complement activation by HSV-1 (project 3) and develop novel herpes vaccines using complement as a natural adjuvant. The use of activation products of complement C3 to target viral proteins to the lymphoid compartment will provide a potent natural adjuvant without the toxic side effects of an inflammatory response. Project 3 and 4 will examine the protective effect against virus infection (project 3) and evaluate the nature of th T and B cell response (project 40 to recombinant virus. In summary the overall project represents a synergistic interaction among investigators with expertise in distinct but overlapping disciplines. The individual projects were designed to take advantage of the availability of specialized reagents and expertise of the other investigators.